Many proliferative conditions are known to be associated with papillomaviruses, in particular varieties of warts, such as condyloma acuminata (anogenital warts) and cervical intraepithelial dysplasia and neoplasia, which can develop into cervical cancer.
Condyloma acuminata is caused by infection with human papillomavirus, usually HPV types 6 and 11, and is the most commonly diagnosed viral sexually transmitted disease in the UK. Significant morbidity is associated with the lesions, and available treament regimes are unsatisfactory, with many patients exhibiting recurrent disease. Other HPV types, particularly 16 and 18, are associated with development of intraepithelial dysplasia and neoplasia which may progress to invasive carcinoma tumours of the cervix and (more rarely) of the vulva, vagina or penis. Furthermore, one study showed cervical intraepithelilal neoplasia in 50% of patients with visible genital warts (PG Walker et al, (1983) Br J Ven Dis 59:120-123).
A proportion (about 20%) of patients with condylomata undergo spontaneous regression of their tumours, apparently reflecting an effective immune response mounted by the host. S Aiba et al ((1986) Cancer 58: 1246-1251) reported that tumour regression was characterised by an active cell-mediated immune response in which CD4+ T lymphocytes and macrophages predominate, consistent with a delayed type hypersensitivity response to foreign antigen.
Vaccines have previously been proposed for prophylaxis and therapy of papillomavirus-associated conditions. Thus for example WO 93/00436 (Cancer Research Campaign Technology: WFH Jarrett et al) concerns the use of papillomavirus protein L2, and of related fragments and fusion proteins, for prophylaxis and therapy of papillomavirus-associated conditions; WO 93/20844 (Cancer Research Campaign Technology: M S Campo et al) relates to vaccine uses of papillomavirus E7 protein; and WO 93/02184 (University of Queensland and CLS Ltd: I Frazer et al: Papilloma Virus Vaccine) relates to papillomavirus-like particles comprising L1 protein or L1 and L2 protein and their use as vaccine.
Furthermore WO 96/00583 (Merck: J J Donnelly et al: Polynucleotide Vaccine for Papillomavirus) describes DNA constructs encoding papilloma virus gene products, capable of being expressed upon direct introduction into animal tissues, as prophylactic pharmaceuticals which can provide immune protection against infection by papilloma virus.
In the field of immunology large numbers of cytokines and accessory substances are known, of which one of the known cytokines is now designated IL-12. WO 92/05256 (Genetics Institute and Wistar Institute: G Trinchieri et al: Natural Killer Stimulatory Factor) describes IL-12 as a human cytokine under the designation natural killer stimulatory factor. WO 92/05256 contains a recommendation, in general terms, to use NKSF or one or both of its subunits or peptide fragments thereof in a suitable pharmaceutical carrier, in "methods for treating cancer, viral infections such as AIDS, bacterial infections and other disease states responsive to the enhanced presence of gamma interferon or GM-CSF production".
EP 0 433 827 (Hoffmann-la Roche: RA Chizzonite et al: Cytotoxic lymphocyte maturation factor and monoclonal antibodies directed thereto) describes IL12 under the designation cytotoxic lymphocyte maturation factor (CLMF). IL-12 has been alternatively designated as natural killer cell stimulatory factor.
Reference in connection with IL-12 is also made to M Kobayashi et al. J Exp Med (Sep 1989) 170(3) 827-845 "Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes"; to A S Stern et al, Proc Nat Acad Sci USA (Sep 1990) 87:6808-6812, "Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells"; and to S F Wolf et al. J Immunol (May 1991) 146(9):3074-3081, "Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells". IL-12 occurs as a heterodimer of two covalently linked polypeptide chains, p40 and p35, the products of distinct genes. IL-12 has been reported as produced by monocytes/macrophages, B cells, mast cells and by NK cells. An IL-12 receptor has been found on activated T cells and activated NK cells, and is a single transmembrane glycoprotein of 70-75 kDa. IL-12 has been reported to promote the growth of activated NK, CD4+ and CD8+ T cell subsets and to increase both antibody dependent cellular cytotoxicity and NK mediated cytotoxicity. IL-12 is also an inducer of interferon-gama (IFN-gamma) which can activate macrophages.
A report of injecting interferon-gamma (one of the cytokines) into genital warts has been made (L J Eron et al, (1986) New Engl J Med vol 315(17); and L Belli et al (Condylomata International Study Group), (1991) J Amer Med Ass, vol 265(20) (May 22/29).).
The prior art leaves it still desirable to seek further treatments for papillomavirus-associated conditions and for the tumours to which these can give rise.